The present invention, in some embodiments thereof, relates to polymeric systems and, more particularly, but not exclusively, to polymeric systems loaded with a bioactive agent, which are designed so as to controllably release the bioactive agent.
Drug-eluting medical devices have become increasingly in demand in the last decade. Drug-eluting medical devices for topical administration, such as skin patches and wound dressing, are commonly used for systemic and local drug delivery, various skin treatments and tissue regeneration. Implantable drug-eluding devices are used to deliver a drug to a target organ or bodily site in fields such as cardiology, tissue regeneration, pain management and cancer treatment.
Drug-delivery systems have been developed over the years for uses in various applications, including topical and systemic treatments. Controlled drug delivery applications include both sustained delivery over days/weeks/months/years and targeted (e.g., to an infected wound, an exposed tissue, a damaged tissue, a tumor, a diseased blood vessel, etc.) delivery on a “one-time” or sustained basis. Controlled release formulations can be used to reduce the amount of drug necessary to cause the same therapeutic effect in patients. The convenience of fewer and more effective doses also increases patient compliance. Over the years of controlled release research, different systems, ranging from coated tablets and gels to biodegradable microspheres and osmotic systems, have been explored experimentally and computationally to get pre-designed release profiles. In many of the controlled release formulations, immediately upon placement in the release medium, an initial large bolus of drug is released before the release rate reaches a stable profile. This phenomenon is typically referred to as “burst release”.
Burst release may be the optimal mechanism of delivery in several instances. One of the current difficulties with burst release is that it is unpredictable, and even when the burst is desired, the amount of burst cannot be significantly controlled. It has been shown that many drugs need to be administered at varying rates, and for some drugs, such as those used at the beginning of wound treatment, an initial burst provides immediate relief followed by prolonged release to promote gradual healing. The food industry have a vested interest in the development of burst release systems where coatings are desired to protect flavors and aromas during processing and storage, but must allow rapid release when the product is consumed. Recent advances in the ability to target specific cells and organs, through either surface modification or implantation, allows the location of the delivery to be highly specific, and either burst or prolonged release may be desired at that site, after the coating has served its purpose of sequestering the drug to protect it from denaturation and first-pass metabolism. In several pulsatile delivery processes, burst release may also be a goal, so that the active agent can be delivered rapidly upon changes in environmental conditions that trigger the release.
Organ and tissue failure or loss, such as in burn wounds, trauma wounds, diabetic ulcers and pressure sores, is one of the most frequent and devastating problems in human healthcare. The skin, being the largest organ in the body, serving many different functions, still possesses some of the most difficult challenges in modern medicine. The moist, warm, and nutritious environment provided by topical wounds, together with a diminished immune function secondary to inadequate wound perfusion, may enable the build-up of physical factors such as devitalized, ischemic, hypoxic, or necrotic tissue and foreign material, all of which provide an ideal environment for bacterial growth. In burns, infection is the major complication after the initial period of shock. Drug-eluting wound dressing is one of the most advanced and effective therapeutic solutions to such medical conditions.
Presently known wound dressings are designed to maintain a moist environment to promote healing by preventing cellular dehydration and encouraging collagen synthesis and angiogenesis. Nevertheless, over-restriction of water evaporation from the wound should be avoided as accumulation of fluid under the dressing may cause maceration and sustain infection. Water vapor transmission rate (WVTR) from skin has been found to vary considerably depending on the wound type and healing stage; increasing from 204 grams per square meter per day for normal skin to 278 and as much as 5138 grams per square meter per day, for first degree burns and granulating wounds, respectively. Therefore, the physical and chemical properties of the dressing should be suited to the type of wound and importantly to the degree of exudation from it.
A range of dressing formats based on films, hydrophilic gels and foams are available or have been investigated. These include, for example, OPTSITE® (Smith&Nephew) and BIOCLUSSIVE® (Johnson & Johnson); carboxymethylcellulose-based INTRASITE GEL® (Smith&Nephew) and alginate-based TEGAGEL® (3M); and LYOFOAM® (Mölnlycke Healthcare) and ALLEVYN® (Smith&Nephew).
The partial efficacy of films and foams has encouraged the development of improved wound dressings that provide an antimicrobial effect by eluting germicidal compounds such as iodine (IODOSORB®, Smith&Nephew), chlorohexidime (BIOPATCH®, Johnson & Johnson) or most frequently silver ions (e.g. ACTICOAT® by Smith&Nephew, ACTISORB® by Johnson & Johnson and AQUACELL® by ConvaTec). Such dressings are designed to provide controlled release of the active agent through a slow sustained release mechanism which helps to avoid toxicity yet ensures delivery of a therapeutic dose to the wound.
Biodegradable film dressings made of lactide-caprolactone copolymers such as Topkin® (Biomet) and Oprafol® (Lohmann & Rauscher) have been made available. Bioresorbable dressing based on biological materials such as collagen and chitosan have been reported to perform better than conventional and synthetic dressings in accelerating granulation tissue formation and epithelialization. However, controlling the release of antibiotics from devices made from these hydrophilic materials is deficient since in most cases the drug's reservoir is depleted in less than two days, resulting in a very short antibacterial effect.
A major area of research in tissue engineering is the development of medical devices that elute bioactive agents such as growth factors, which upon placement of such device, recruit cells from the body thereto, and thus enable tissue formation therein. Typically the administration of growth factors is problematic, due to their poor in vivo stability. It is therefore necessary to develop systems with controlled delivery of bioactive agents that can achieve prolonged availability as well as protection of these bioactive agents, which may otherwise undergo rapid proteolysis.
The main obstacle to successful incorporation and delivery of small molecules, as well as proteins, from scaffolds is their inactivation during the process of scaffold manufacture due to exposure to high temperatures or harsh chemical environments. Methods that minimize protein inactivation must therefore be developed. Three approaches to protein (growth factor) incorporation into bioresorbable scaffolds have recently been presented: (i) adsorption onto the surface of the scaffold [Elcin A E, et al., Tissue Eng 2006, 12, p. 959-68]; (ii) composite scaffold/microsphere structures [Zhu X H, et al. J Biomed Mater Res A, 2009, 89(2), p. 411-23; Wei G, et al., J Controlled Release 2006; 112(1), p. 103-10]; and (iii) freeze-drying of inverted emulsions. The third method is briefly described below.
Emulsions are metastable colloids formed by two immiscible fluids, where one is dispersed in the other in the presence of surface-active agents (surfactants) [Bibette J.; Emulsion Science: Basic Principles: an overview; Berlin, Springer Verlag; 2002, chp. 5-6]. Inverted emulsions are composed of water droplets dispersed in a continuous oil (organic) phase. Emulsions are obtained by shearing two immiscible fluids, leading to the fragmentation of one phase into the other. They are metastable and their lifetime may vary considerably depending on the temperature and their composition. The instability is due to the large interfacial area, which results in a large surface energy that is associated with finely dispersed systems [Becher P. Encyclopedia of emulsion technology, New York, Marcel Dekker; 1988, chp. 1-2]. The technique of freeze-drying inverted emulsions is unique in being able to preserve the liquid structure in solids. Also, it is important to note that incorporation of bioactive molecules is carried out during the scaffold-production process. This fabrication process enables the incorporation of both water-soluble and water-insoluble drugs into the film in order to obtain an “active implant” that releases drugs to the surrounding in a controlled manner. Water-soluble bioactive agents are incorporated in the aqueous phase of the inverted emulsion, whereas water-insoluble drugs are incorporated in the organic (polymer) phase. Sensitive bioactive agents, such as proteins, can also be incorporated in the aqueous phase. This prevents their exposure to harsh organic solvents and enables the preservation of their activity. Whang et al. [Whang K, et al., Polymer, 1995, 36(4), p. 837-42; Whang K et al., J Biomed Mater Res, 1998, 42(4), p. 491-9] used this method to prepare poly(DL-lactic-co-glycolic acid) (PDLGA or PLGA) scaffolds loaded with a recombinant human bone morphogenetic protein (rhBMP-2) and investigated the effect of the rhBMP-2 release in vivo using a rat model. The rhBMP-2-incorporated scaffold induced bone formation, which confirmed the preserved bioactivity of the rhBMP-2 released from the scaffold. Contact radiography, radiomorphometry, histology and histomorphometry revealed significantly more bone in the rhBMP-2 implants than in the controls.
Nanoemulsions are thermodynamically stable when the surface tension is reduced to approximately zero, or metastable in very small-scale emulsions. The literature on nanoemulsion formation refers to two main techniques: dispersion (high-energy emulsification) and condensation (low-energy emulsification). Dispersion techniques use energy input, generally from mechanical devices such as rotor-stator systems, high shear stirring, high pressure homogenizers, and ultrasound generators, whereas condensation methods use chemical energy stored in the components (usually surfactants). The small droplet size makes nanoemulsions stable against coalescence and creaming. Most publications and applications of nanoemulsions are related to the oil-in-water (O:W) type. Only a few recent publications described water-in-oil (W:O) nanoemulsions, which are also referred to in the art as inverted emulsions [N. Uson, et al., Colloids Surf A, 2004, 250, p. 415; S. Freitas et al., Eur. J. Pharm. Biopharm., 2005, 61, p. 181; and Ham, H. T. et al., J. Phys. Chem. B, 2006, 110, p. 13959].
The freeze-drying of inverted emulsions technique is unique in being able to preserve the liquid structure in solids in order to produce highly porous nanostructured films that can be used as basic elements or parts of various implants and scaffolds for tissue regeneration. This fabrication process enables the incorporation of both water-soluble and water-insoluble drugs into the film in order to obtain an “active implant” that releases drugs to the surrounding in a controlled manner and therefore induces healing effects in addition to its regular role (of support, for example). Water-soluble bioactive agents are incorporated in the aqueous phase of the inverted emulsion, whereas water-insoluble drugs are incorporated in the organic (polymer) phase. Sensitive bioactive agents, such as proteins, can also be incorporated in the aqueous phase. This prevents their exposure to harsh organic solvents and enables the preservation of their activity.
The presence of surface-active agents (surfactants) is necessary for stabilizing an emulsion since they reduce the interfacial tension between the two immiscible phases. Proteins are widely used as emulsion stabilizers in the food industry [K. Whang, T. K. et al., Biomaterials, 2000, 21, p. 2545; Tcholakova, S. et al., Adv. Colloid Interface Sci., 2006, 123, p. 259].
It has been reported that metastable W:O nanoemulsions can be stabilized by bovine serum albumin (BSA) [Sarker, D. K., Curr. Drug Deliv., 2005, 2, p. 297; Whang, K. et al., Biomaterials, 2000, 21, p. 2545; Yang, Y. Y. et al., Biomaterials, 2001, 22, p. 231]. Hydrophilic polymers, such as poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG), act as surfactants due to their amphiphilic molecular structure, thus increasing the affinity between the aqueous and organic phases [Liu, Y. et al., J. Control. Release 2002, 83, 147; Castellanos, I. J. et al., J. Pharm. Pharmacol., 2005, 57, p. 1261; and Delgado, A. et al., Eur. J. Pharm. Biopharm., 2000, 50, p. 227].
U.S. Patent Application having Publication No. 20070134305, by the present inventor, which is incorporated by reference as if fully set forth herein, teaches composite structures, composed of a fibril core and a polymeric coat, which are capable of encapsulating both hydrophobic and hydrophilic bioactive agents while retaining the activity of these agents and favorable mechanical properties of the core fiber. These composite fibers, comprising a coat made of a freeze-dried layer of an emulsion containing a biodegradable polymer and the drug(s), can be used to construct medical devices and disposable articles.
U.S. Patent Application having Publication No. 20110091515, of which the present inventor is a co-author, which is incorporated by reference as if fully set forth herein, teaches composite structures composed of a mesh device as a core structure, being a medical device or article, and a porous polymeric coat and designed capable of encapsulating bioactive agents while retaining the activity of these agents.
The structures disclosed in U.S. Patent Applications having Publication Nos. 20070134305 and 20110091515 are useful in applications such as tissue engineering where encapsulation of biomolecules such as growth factors and cells can be effected without compromising bioactivity or mechanical strength.
Additional background art includes Zilberman, M. et al., J. Biomater. Appl., 2008, 22(5), p. 391-407; Zilberman et al., J. Biomater. Appl., 2009, 23(5), p. 385-406; and Shifrovitch et al., J. Periodontol, 2009, 80(2), p. 330-337.